Viral inactivation by soluble receptor proteins. Like other viruses, HIV-1 can be inactivated by the soluble recombinant form of its cell surface receptor (CD4) or by a hybrid fusion protein, CD4-Ig, containing the CD4 binding site fused to the Fc constant region of immunoglobulin. To study the antiviral effect of CD4-Ig, we have measured virus survival in the HIV-1 plaquing assay, as well as the corresponding level of CD4-Ig binding, measured by immunofluorescence. By comparing these two measurements, we have determined the relationship between receptor binding and viral inactivation. The results were analyzed according to a critical binding model, in which viruses binding greater than a critical amount of CD4-Ig would be inactivated, while those binding less than or equal to the critical amount would remain completely viable. The experimental points fit within the predicted curves for a critical binding level of about 6 gp120 binding sites per virus. Since gp120 appears to form trimers on the surface of the virus, CD4-Ig binding to 6 of the 72 trimeric gp120 spikes can inactivate the entire virus. These results are consistent with a triggering mechanism for inactivation. They may also relate to neutralizing antibodies, since the CD4 binding site on gp120 is also a target for group-specific neutralizing antibodies found in the sera of most infected patients. Our hypothesis, that neutralizing antibodies which bind at the same site inactivate virus by the same mechanism, will be tested in the coming year.